CN108602810B - Suvorexane intermediate compound and preparation method thereof - Google Patents
Suvorexane intermediate compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a suvorexant synthesis process and a preparation method of new compounds of formulas II, III, IV and V or salts and intermediates thereof for preparing suvorexant. The preparation method obtains chiral compounds II, III, IV and V through chiral starting material synthesis, can be used for the synthesis of suvorexant, and has the advantages of simple operation, low cost, mild reaction conditions, simple post-treatment, easy purification, high yield, high ee value and easy industrialization. Wherein R represents benzyl, allyl, 1-phenylethyl or benzyl wherein the carbon atoms in the positions 2 to 6 are optionally substituted, such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl, 3-fluorobenzyl.
Description
The present application claims priority from the chinese patent application filed on 1/2/2016 under the name of the chinese patent office, application No. 201610070443.7, entitled "suvorexant intermediate compound and process for its preparation", the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the technical field of drug synthesis, and provides a suvorexant synthesis process, and a new compound formula II, III, IV, V for preparing suvorexant, or a salt and an intermediate preparation method thereof.
Background
Orexins (orexin) are neuropeptides that are involved in the regulation of the sleep-wake cycle and play an important role in maintaining human arousal. Suvorexant (Suvorexant) is an Orexins receptor antagonist, and the drug achieves the effect of improving the sleep of patients by blocking the transmission of Orexins. 8/13/2014, suvorexant (trade name belsmora), a merck new insomnia drug approved by the united states Food and Drug Administration (FDA), is marketed.
The following documents report synthetic routes to this compound:
(1) the synthetic route reported in US2008/132490 is as follows:
(2) the synthetic route reported by org. Process Res. Dev.2011, 15, 367-375 is as follows:
(3) the synthetic routes reported in WO2012148553 and j.am.chem.soc.2011, 133, 8362-:
the three routes described above have the following disadvantages: the starting material uses a highly toxic compound methyl vinyl ketone which has strong irritation to eyes, skin, mucous membrane and upper respiratory tract and is not easy to operate when in use; in the preparation process of the first route, chiral column resolution is needed, the first route is not suitable for industrial mass production, and the overall yield of the first route is low; a chiral resolution reagent is needed in the second route, the yield in the process is low, a large amount of materials are wasted, and the cost is increased; and in the third route, heavy metal ruthenium is adopted to catalyze asymmetric reductive amination, so that the cost is high and the environment is not friendly.
(4) WO2015008218 reports the preparation of suvorexant using specifically N-Boc N' -benzylethylenediamine as starting material:
the route was prepared using 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), ketene, cyanuric chloride, Cu (OAc)2And the like, and, in addition, wherein (+)2 is used,the 3-dibenzoyl-D-tartaric acid is resolved, but an ee value is not disclosed, the whole process route is longer, the reaction operation is more complicated, and the resolution of a general resolving agent is not kinetic resolution, the atom utilization rate is not high, the cost of the route is increased, and the commercial production is not facilitated.
The specific reaction formula is as follows:
therefore, the method for synthesizing the new suvorexant and the intermediate compound thereof is developed to overcome the defects of the prior art and has very important significance.
Disclosure of Invention
The invention relates to a suvorexant synthesis process and a preparation method of new compounds of formulas II, III, IV and V or salts and intermediates thereof for preparing suvorexant.
The general synthetic route is as follows:
the experimental route is as follows: reacting a compound of a formula I with amino acid protected by Boc through a condensing agent under alkaline conditions to obtain a compound of a formula II, removing tert-butyloxycarbonyl from the compound of the formula II under acidic conditions, and then carrying out cyclization under alkaline conditions to obtain a compound of a formula III, carrying out hydrogenation reduction on the compound of the formula III to obtain a compound of a formula IV, reacting the compound of the formula IV with 2, 5-dichlorobenzoxazole under alkaline conditions to obtain a compound of a formula V, removing R groups from the compound of the formula V under the action of a catalyst to obtain a compound of a formula VI, and reacting the compound of the formula VI with 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid under alkaline conditions through the action of the condensing agent to obtain Suvorexane.
The specific preferred technical scheme is as follows:
the invention provides a preparation method of a compound shown in a formula II, which comprises the following steps:
carrying out condensation reaction on a compound shown in a formula I and glycine protected by Boc in an organic solvent under the action of an alkaline condition and a condensing agent to obtain a compound shown in a formula II;
r represents benzyl, allyl, 1-phenylethyl or benzyl optionally substituted on the carbon atoms from position 2 to 6 such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
wherein the organic solvent used in the condensation reaction to prepare the compound of formula II is selected from dichloromethane, tetrahydrofuran or N, N-dimethylformamide, preferably N, N-dimethylformamide;
wherein the base used in the condensation reaction to prepare the compound of formula II is selected from triethylamine, 1, 8-diazabicyclo (5.4.0) undec-7-ene, 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, N-methylpiperazine, piperidine, sodium bicarbonate, potassium carbonate or sodium hydride, preferably triethylamine or N-methylmorpholine;
wherein the condensation reaction for preparing the compound of formula II uses a condensing agent selected from the group consisting of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and 1-hydroxy-7-azobenzotriazol, preferably a combination of 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
The invention provides a preparation method of a compound shown in a formula III, which comprises the following steps:
removing tert-butyloxycarbonyl from the compound of formula II in an organic solvent under the action of an acid to obtain corresponding amine or salt thereof; then carrying out cyclization reaction under the action of alkali to obtain a compound shown in a formula III;
r represents benzyl, allyl, 1-phenylethyl or benzyl optionally substituted on the carbon atoms from position 2 to 6 such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
wherein the organic solvent used in the reaction of removing tert-butyloxycarbonyl from the compound of formula II is selected from ethyl acetate, dichloromethane, N-dimethylformamide, acetonitrile, toluene, methanol or ethanol;
wherein the acid used in the reaction for removing the tert-butyloxycarbonyl group from the compound of the formula II is selected from acids such as HCl or trifluoroacetic acid;
wherein the base used in the reaction for removing the tert-butyloxycarbonyl group from the compound of the formula II is selected from magnesium alkoxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium borohydride, potassium tert-butoxide and triethylamine;
the invention provides a preparation method of a compound shown in formula IV, which comprises the following steps:
the compound of the formula III is subjected to reduction reaction under the action of a reducing agent to obtain a compound IV or salt thereof,
r represents benzyl, allyl, 1-phenylethyl or benzyl optionally substituted on the carbon atoms from position 2 to 6 such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
wherein the solvent for the reduction reaction is selected from dichloromethane or tetrahydrofuran;
wherein the reducing agent used in the reduction reaction is selected from borane, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum tetrahydroborate or sodium hydride.
The invention provides a preparation method of a compound shown in a formula V, which comprises the following steps:
under the action of alkali, the compound of the formula IV and 2, 5-dichlorobenzoxazole are subjected to C-N coupling reaction to obtain a compound of the formula V or a salt thereof,
r represents benzyl, allyl, 1-phenylethyl or benzyl optionally substituted on the carbon atoms from position 2 to 6 such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
wherein the solvent for the C-N coupling reaction is selected from N, N-dimethylformamide, toluene, tetrahydrofuran or acetonitrile;
wherein the base used in the C-N coupling reaction is selected from triethylamine, N-methylmorpholine, piperidine, N-methylpiperazine, sodium bicarbonate, potassium carbonate and sodium hydride.
The invention provides a preparation method of a compound of formula VI, which comprises the following steps:
in an organic solvent, under the action of a catalyst, the compound shown in the formula V is subjected to deprotection reaction to remove R protecting group,
r represents benzyl, allyl, 1-phenylethyl or benzyl optionally substituted on the carbon atoms from position 2 to 6 such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
wherein the organic solvent used for deprotection reaction is selected from C1-C4 lower alcohol or halogenated hydrocarbon, preferably methanol, ethanol or 1, 2-dichloroethane;
wherein the catalyst used for the deprotection reaction is selected from chloroformate catalyst or palladium catalyst, wherein the chloroformate catalyst is preferably chloro ethyl chloroformate, and the palladium catalyst is preferably Pd/C, Pd (OH)2/C or PdCl2/C。
The invention also provides a process for the preparation of suvorexant from a compound of formula VI, comprising the steps of:
carrying out condensation reaction on a compound shown in the formula VI and 5-methyl-2- (2H-1, 2, 3-triazole-2-yl) benzoic acid in a condensing agent, alkali and an aprotic solvent to obtain suvorexant, wherein the reaction formula is as follows:
wherein the aprotic solvent used in the condensation reaction for preparing suvorexant is selected from aprotic solvents such as acetonitrile, tetrahydrofuran, toluene, dichloromethane or N, N-dimethylformamide, preferably N, N-dimethylformamide;
wherein the condensing agent used for the condensation reaction to prepare suvorexant is selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-diisopropylcarbodiimide, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and 1-hydroxy-7-azobenzotriazol, preferably a combination of 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
wherein the base used in the condensation reaction for the preparation of suvorexant is selected from triethylamine, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine or N-methylpiperazine or piperidine, preferably triethylamine or N-methylmorpholine.
In addition, the invention also relates to four novel compounds for preparing suvorexant (suvorexant), namely a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V or salts thereof;
r represents benzyl, allyl, 1-phenylethyl or benzyl with 2-6 carbon atoms optionally substituted such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl, 3-fluorobenzyl;
the compound of formula II is preferably: (R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate;
the compound of formula III is preferably: (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione;
the compound of formula IV is preferably: (R) -1-benzyl-7-methyl-1, 4-diazepane;
the compound of formula V is preferably: 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole.
The invention has the beneficial technical effects that: compared with the prior art, the invention designs the 5-methyl-2- (2H-1, 2, 3-triazole-2-yl) benzoic acid with higher price to be used in the last step, improves the atom utilization rate of the compound and greatly reduces the production cost; meanwhile, the method avoids the use of flammable and virulent compounds methyl vinyl ketone or ketene to construct a diazacycloheptane framework, and obtains the Suvorexane intermediate with the required configuration through a chiral starting material; the method has the advantages of mild reaction conditions, simple post-treatment, high yield, high ee value, easy industrialization and the like.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1:
synthesis of (R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate
(R) -methyl-3- (benzylamino) -butyrate (40mmol) was added to a flask, dissolved in 80ml of anhydrous DMF, and the system was cooled to 0 to 5 ℃ and added with 1-hydroxybenzotriazole (48mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (48mmol), N-methylmorpholine (100mmol) and N- (tert-butoxycarbonyl) glycine (44mmol) with stirring, followed by reaction at room temperature for 6 hours. Adding a citric acid solution with the mass fraction of 10%, extracting with ethyl acetate, washing an organic phase with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing with ethyl acetate and petroleum ether to obtain the (R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate with the yield of 93%.1H NMR(400MHz，cdcl3)δ7.35(t，J＝7.3Hz，1H)，7.31-7.11(m，4H)，5.56(d，J＝38.0Hz，1H)，4.63-4.31(m，3H)，4.23-4.07(m，1H)，3.97-3.83(m，1H)，3.57(d，J＝53.8Hz，3H)，2.80(dd，J＝15.6，7.4Hz，1H)，2.60-2.47(m，1H)，1.44(d，J＝16.0Hz，9H)，1.26-1.21(m，3H)；MS(ESI)m/z 365.20([M+H]+)。
(R) -methyl-3- (allylamino) -butyrate (40mmol), (R) -methyl-3- (1-phenylethylamino) -butyrate (40mmol), (R) -methyl-3- (4-methoxybenzylamino) -butyrate (40mmol), (R) -methyl-3- (4-chlorobenzylamino) -butyrate (40mmol), (R) -methyl-3- (3-fluorobenzylamino) -butyrate (40mmol), (R) -methyl-3- (2-methylphenylamino) -butyrate (40mmol), (R) -methyl-3- (4-nitrophenylamino) -butyrate (40mmol) were synthesized according to the same method as the above-described method in this example, respectively -3- (N-allyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (1-phenylethyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (4-methoxybenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (4-chlorobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (3-fluorobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, and (d) methyl-3- (N- (3-fluorobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (2-methylbenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate, (R) -methyl-3- (N- (4-nitrobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate.
Example 2:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% by mass methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, potassium carbonate (20mmol) was added, and the reaction was carried out overnight at 110 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 92% yield.1H NMR(400MHz，cdcl3)δ7.40-7.17(m，5H)，6.24(s，1H)，5.24(d，J＝15.1Hz，1H)，4.25(dd，J＝17.5，3.0Hz，1H)，4.09(d，J＝15.1Hz，1H)，4.00(dd，J＝17.5，7.1Hz，1H)，3.72(td，J＝6.6，3.4Hz，1H)，3.02(dd，J＝15.0，3.2Hz，1H)，2.50(m，1H)，1.38(d，J＝6.6Hz，3H)；MS(ESI)m/z 233.10([M+H]+)。
Example 3:
synthesis of (R) -1-allyl-7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N-allyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, potassium carbonate (20mmol) was added, and the reaction was carried out overnight at 110 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid with a yield of 90%.
Example 4:
synthesis of (R) -1- (1-phenylethyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (1-phenylethyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, and sodium hydride (40mmol) was added to react at 110 ℃ overnight. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 85% yield.
Example 5:
synthesis of (R) -1- (4-methoxybenzyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (4-methoxybenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, sodium carbonate (20mmol) was added, and the reaction was carried out overnight at 110 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 85% yield.
Example 6:
synthesis of (R) -1- (4-chlorobenzyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (4-chlorobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, and potassium tert-butoxide (40mmol) was added to react at 110 ℃ overnight. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 88% yield.
Example 7:
synthesis of (R) -1- (3-fluorobenzyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (3-fluorobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, triethylamine (40mmol) was added, and the reaction was carried out overnight at 80 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 80% yield.
Example 8:
synthesis of (R) -1- (2-methylbenzyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (2-methylbenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, potassium carbonate (20mmol) was added, and the reaction was carried out overnight at 110 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid in 93% yield.
Example 9:
synthesis of (R) -1- (4-nitrobenzyl) -7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N- (4-nitrobenzyl) -2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, potassium carbonate (20mmol) was added, and the reaction was carried out overnight at 110 ℃. After cooling to room temperature, the solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spin-drying to give a white solid with a yield of 89%.
Example 10:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of ethyl acetate, added with 40ml of a 45 mass% ethyl acetate hydrochloride solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry methanol, and sodium methoxide (15mmol) was added and reacted overnight at 110 ℃ under nitrogen. Quenching with saturated ammonium chloride solution, adding dichloromethane for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and spin-drying to obtain white solid with yield of 94%.
Example 11:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was charged into a flask, dissolved with 10ml of dichloromethane, added with 40ml of a dichloromethane solution containing 20% by mass of trifluoroacetic acid, and reacted at 25 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry toluene, sodium hydride (15mmol) was added and the reaction was carried out overnight at 110 ℃ under nitrogen. Quenching with saturated ammonium chloride solution, adding dichloromethane for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and spin-drying to obtain white solid with the yield of 91%.
Example 12:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione
(R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate (10mmol) was added to a flask, dissolved in 10ml of methanol, added with 40ml of 30% by mass methanol-hydrochloric acid solution, and reacted at 50 ℃ for 6 hours. Concentrating under reduced pressure, and evaporating to obtain yellow oil. This was dissolved in 50ml of dry methanol, triethylamine (30mmol) was added and the reaction was carried out overnight at 60 ℃ under nitrogen. Quenching with saturated ammonium chloride solution, adding dichloromethane for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and spin-drying to obtain white solid with yield of 90%.
Example 13:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepane
Dissolving (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione (10mmol) in 30ml of dried tetrahydrofuran, adding the mixture into 30ml of dried tetrahydrofuran containing 2g of sodium borohydride (54mmol) in an ice water bath, dropwise adding 40ml of dried tetrahydrofuran containing 24mmol of iodine under the protection of nitrogen, and refluxing overnight. Cooling to 0 deg.C, adding 15ml 2M HCl solution, quenching, adding 20ml 3M sodium hydroxide solution, separating, extracting the water phase with dichloromethane twice, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the dried solvent under reduced pressure to obtain colorless oily liquid with yield of 89%.1H NMR(400MHz，cdcl3)δ7.31-7.15(m，5H)，3.74-3.56(m，3H)，3.29(t，J＝6.6Hz，2H)，3.04-2.94(m，2H)，2.85-2.76(m，1H)，2.59(dd，J＝15.5，3.3Hz，1H)，2.23-2.11(m，1H)，1.92-1.80(m，1H)，1.02(d，J＝6.3Hz，3H)；MS(ESI)m/z 205.10([M+H]+)。
Example 14:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepane
(R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione (10mmol) was dissolved in 100ml of dry tetrahydrofuran, lithium aluminum hydride (60mmol) was added in portions in an ice-water bath, and the mixture was stirred overnight at 25 ℃. Cooling to-5 deg.C, adding 2ml ice water to quench reaction, adding 20ml 3M sodium hydroxide solution, separating, extracting the water phase twice with dichloromethane, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the dry solvent under reduced pressure to obtain colorless oily liquid with yield of 90%.
Example 15:
synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepane
(R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione (10mmol) was dissolved in 100ml of dry tetrahydrofuran, borane dimethylsulfide solution (20mmol) was added dropwise in an ice-water bath, and the mixture was stirred at 65 ℃ overnight. Cooling to-5 deg.c, adding 2ml methanol to quench reaction, regulating pH to 3, stirring for 3 hr, regulating pH to 10 with sodium carbonate, extracting water phase with dichloromethane three times, combining organic phases, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, suction filtering, and vacuum concentrating to obtain colorless oily liquid in 87% yield.
Example 16:
synthesis of 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
To a solution of (R) -1-benzyl-7-methyl-1, 4-diazepane (10mmol) in 40ml of DMF was added 2, 5-dichlorobenzoxazole (10mmol) and triethylamine (25mmol), and the mixture was heated to 75 ℃ for reaction for 3 hours. Cooling to room temperature, adding saturated sodium bicarbonate solution, extracting with ethyl acetate, washing the obtained organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain colorless oily liquid with yield of 95%.1H NMR(400MHz，cdcl3)δ7.40-7.25(m，5H)，7.23(dd，J＝7.3，2.2Hz，1H)，7.12(d，J＝8.4Hz，1H)，6.94(dd，J＝8.4，2.1Hz，1H)，3.92-3.82(m，2H)，3.76-3.56(m，4H)，3.13(ddd，J＝8.1，6.8，3.9Hz，1H)，2.96(ddd，J＝14.6，6.9，3.1Hz，1H)，2.81(ddd，J＝14.6，7.4，3.2Hz，1H)，2.20-2.11(m，1H)，1.84-1.76(m，1H)，1.13(d，J＝6.7Hz，3H)；MS(ESI)m/z 356.10([M+H]+)。
Example 17:
synthesis of 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
To a 40ml toluene solution of the synthesis of (R) -1-benzyl-7-methyl-1, 4-diazepane (10mmol) was added 2, 5-dichlorobenzoxazole (10mmol), potassium carbonate (25mmol), and the temperature was raised to 75 ℃ for reaction for 3 h. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the obtained organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain colorless oily liquid with yield of 89%.
Example 18:
synthesis of 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
To a 40ml tetrahydrofuran solution of (R) -1-benzyl-7-methyl-1, 4-diazepane (10mmol) was added 2, 5-dichlorobenzoxazole (10mmol), N-methylmorpholine (25mmol), and the temperature was raised to 75 ℃ for reaction for 3 h. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the obtained organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain colorless oily liquid with yield of 85%.
Example 19:
synthesis of 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
To a solution of (R) -1-benzyl-7-methyl-1, 4-diazepane (10mmol) in 40ml of acetonitrile was added 2, 5-dichlorobenzoxazole (10mmol) and sodium hydrogen carbonate (25mmol), and the mixture was heated to 75 ℃ for reaction for 3 hours. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the obtained organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain colorless oily liquid with yield of 75%.
Example 20:
synthesis of 5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
Reacting 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl]Benzoxazole (5mmol) is dissolved in 25ml of 1, 2-dichloroethane, the temperature is reduced to 0-5 ℃ in an ice-water bath, chloroethyl chloroformate (12.5mmol) is added and stirred for 1h at the temperature, and then the system is heated to 80 ℃ and stirred overnight. After cooling to room temperature and concentration of the solvent under reduced pressure, the residue was dissolved in 25ml of methanol and stirred at 70 ℃ for 3 hours. Adding a sodium bicarbonate solution with the mass fraction of 5%, extracting twice by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain an oily liquid with the yield of 92%. MS (ESI) M/z 266.10([ M + H)]+)。
Example 21:
synthesis of 5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole
Reacting 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl]Benzoxazole (5mmol) was dissolved in 50ml of ethyl acetate, 10% by mass of Pd/C (0.1M) was added thereto, and after three times of replacement with hydrogen, the mixture was reacted at 50 ℃ overnight. Cooling to room temperature, filtering, decompressing and concentrating to obtain oily liquid with the yield of 45 percent. MS (ESI) M/z 266.10([ M + H)]+)。
Example 22:
synthesis of suvorexant
Reacting 5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl]Benzoxazole (10mmol) is dissolved in 50ml of anhydrous DMF, the system is cooled to 0-5 ℃, 1-hydroxybenzotriazole (11mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (11mmol), dried triethylamine (25mmol) and 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid (10.5mmol) are added with stirring, and then the temperature is raised to 50 ℃ for reaction for 6H. Adding a citric acid solution with the mass fraction of 10%, extracting with ethyl acetate, washing an organic phase with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing the obtained product with isopropyl acetate and n-heptane to obtain suvorexant, wherein the yield is 83% and the ee value is 99.9%.m.p.：128～129℃，MS(ESI)m/z 451.20([M+H]+)。
Example 23:
synthesis of suvorexant
5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole (75mmol) was dissolved in N, N-dimethylformamide (75ml), and after the system temperature was lowered to 0 to 5 ℃, 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid (79mmol), HOAt (82.8mmol), EDCI (82.8mmol) and triethylamine (188mmol) were added, followed by natural warming and stirring at room temperature overnight. Adding a citric acid solution with the mass fraction of 10%, extracting with ethyl acetate, washing an organic layer with a 5% sodium carbonate solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating and drying to obtain the suvorexant, wherein the yield is 97%, and the ee value is 99.8%.
Example 24:
synthesis of suvorexant
5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole (75mmol) was dissolved in tetrahydrofuran (75ml), and after the system temperature was lowered to 0 to 5 ℃, 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid (79mmol), HOBt (82.8mmol), EDCI (82.8mmol) and triethylamine (188mmol) were added, followed by natural warming and stirring at room temperature overnight. Adding a citric acid solution with the mass fraction of 10%, extracting with ethyl acetate, washing an organic layer with a sodium carbonate solution with the mass fraction of 5%, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating and drying to obtain the suvorexant with the yield of 92% and the ee value of 99.9%.
Example 25:
synthesis of suvorexant
5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole (75mmol) was dissolved in dichloromethane (75ml), and after the system temperature was lowered to 0 to 5 ℃, 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid (79mmol), HOBt (82.8mmol), EDCI (82.8mmol) and triethylamine (188mmol) were added, followed by natural warming and stirring at room temperature overnight. Adding 10% citric acid solution, extracting with ethyl acetate, washing the organic layer with 5% sodium carbonate solution, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, and drying to obtain suvorexant with yield of 93% and ee value of 99.9%.
Claims (12)
1. A process for preparing a compound of formula VI comprising the steps of:
in an organic solvent, under the action of a catalyst, the compound shown in the formula V is subjected to deprotection reaction to remove R protecting group,
wherein R represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl; the organic solvent used for the deprotection reaction is selected from C1-C4Lower alcohols or halogenated hydrocarbons of (a); the catalyst used for the deprotection reaction is selected from a chloroformate catalyst or a palladium catalyst.
2. The production method according to claim 1, wherein the organic solvent used for the deprotection reaction is methanol, ethanol or 1, 2-dichloroethane.
3. The method of claim 1, wherein said chloroformate catalyst is chloroethyl chloroformate.
4. The production method according to claim 1, wherein the palladium-based catalyst is Pd/C, Pd (OH)2/C or PdCl2/C。
5. A process for the preparation of a compound of formula V as defined in claim 1, comprising the steps of:
under the action of alkali, the compound of the formula IV and 2, 5-dichlorobenzoxazole are subjected to C-N coupling reaction to obtain a compound of a formula V,
wherein R represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl; the solvent used in the C-N coupling reaction is selected from N, N-dimethylformamide, toluene, tetrahydrofuran and acetonitrile; the base used in the C-N coupling reaction is selected from triethylamine, N-methylmorpholine, piperidine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium carbonate and sodium hydride.
6. A process for the preparation of a compound of formula IV as defined in claim 5, comprising the steps of:
the compound of the formula III is subjected to reduction reaction under the action of a reducing agent to obtain a compound IV,
r represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl; the solvent used for the reduction reaction is selected from dichloromethane or tetrahydrofuran; the reducing agent used in the reduction reaction is selected from borane, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum tetrahydroborate or sodium hydride.
7. A process for the preparation of a compound of formula III as defined in claim 6, comprising the steps of:
removing tert-butyloxycarbonyl from the compound of formula II in an organic solvent under the action of an acid to obtain corresponding amine; then carrying out cyclization reaction under the action of alkali to obtain a compound shown in a formula III;
r represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl; wherein the organic solvent used in the reaction of removing tert-butyloxycarbonyl from the compound of formula II is selected from ethyl acetate, dichloromethane, N-dimethylformamide, acetonitrile, toluene, methanol or ethanol; wherein the acid used in the reaction for removing the tert-butyloxycarbonyl group from the compound of formula II is selected from HCl or trifluoroacetic acid; wherein the base used in the cyclization reaction of the compound of formula II is selected from the group consisting of magnesium alkoxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium borohydride, potassium tert-butoxide, and triethylamine.
8. A process for the preparation of a compound of formula II as defined in claim 7, comprising the steps of:
carrying out condensation reaction on a compound shown in a formula I and glycine protected by Boc in an organic solvent under the action of a condensing agent to obtain a compound shown in a formula II;
r represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl; the solvent used in the condensation reaction to prepare the compound of formula II is selected from dichloromethane, tetrahydrofuran or N, N-dimethylformamide; the base used in the condensation reaction to prepare the compound of formula II is selected from triethylamine, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, N-methylpiperazine, piperidine, sodium bicarbonate and potassium carbonate; the condensing agent used in the condensation reaction for preparing the compound of formula II is selected from 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and 1-hydroxy-7-azobenzotriazol.
9. The process according to claim 8, wherein the base used in the condensation reaction for preparing the compound of formula II is triethylamine or N-methylmorpholine.
10. The production method as described in claim 8, wherein the condensing agent used in the condensation reaction for producing the compound of the formula II is a combination of 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
11. A compound of formula II, formula III, formula IV or formula V:
r represents benzyl, allyl, 1-phenylethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl.
12. The compound of claim 11, wherein:
the compounds of formula II are: (R) -methyl-3- (N-benzyl-2- ((tert-butoxycarbonyl) amino) acetamido) butyrate;
the compound of formula III is: (R) -1-benzyl-7-methyl-1, 4-diazepan-2, 5-dione;
the compound of formula IV is: (R) -1-benzyl-7-methyl-1, 4-diazepane;
the compounds of formula V are: 5-chloro-2- [ (5R) -hexahydro-4-benzyl-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole.
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| CN110272925B (en) * | 2018-03-16 | 2021-11-23 | 中国科学院天津工业生物技术研究所 | Enzymatic preparation method of suvorexant key intermediate |
| CN111138333B (en) * | 2018-11-02 | 2023-05-23 | 上海复星星泰医药科技有限公司 | Preparation method of (R) -2- (2, 5-difluorophenyl) -pyrrolidine |
| CN109912519B (en) * | 2019-03-29 | 2022-07-05 | 成都美域高制药有限公司 | Synthetic method of suvorexant intermediate |
| CN112574181A (en) * | 2019-09-30 | 2021-03-30 | 天津药业研究院股份有限公司 | Preparation method and application of suvorexant intermediate |
| CN114685560B (en) * | 2020-12-31 | 2024-05-14 | 沈阳药科大学 | Synthesis and application of phosphoramidite monomer containing piperidine skeleton and oligonucleotide |
| CN113072541B (en) * | 2021-04-02 | 2022-07-08 | 山东四环药业股份有限公司 | Preparation method of targeted drug BLU-667 |
| CN113929673A (en) * | 2021-09-03 | 2022-01-14 | 湖南华腾医药有限公司 | Continuous flow micro-reaction synthesis method of suvorexant intermediate |
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| WO2008069997A1 (en) * | 2006-12-01 | 2008-06-12 | Merck & Co., Inc. | Substituted diazepan compounds as orexin receptor antagonists |
| WO2012148553A1 (en) * | 2011-03-03 | 2012-11-01 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| WO2013169610A1 (en) * | 2012-05-09 | 2013-11-14 | Merck Sharp & Dohme Corp. | Process for the preparation of an intermediate for an orexin receptor antagonist |
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| WO2016020406A1 (en) | 2014-08-04 | 2016-02-11 | Sandoz Ag | Novel routes of synthesis for the preparation of suvorexant |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008069997A1 (en) * | 2006-12-01 | 2008-06-12 | Merck & Co., Inc. | Substituted diazepan compounds as orexin receptor antagonists |
| WO2012148553A1 (en) * | 2011-03-03 | 2012-11-01 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| WO2013169610A1 (en) * | 2012-05-09 | 2013-11-14 | Merck Sharp & Dohme Corp. | Process for the preparation of an intermediate for an orexin receptor antagonist |
Non-Patent Citations (3)
| Title |
|---|
| Facile synthesis of suvorexant,an orexin receptor antagonist,via a chiral diazepane intermediate;Yin Chen等;《Chinese Chemical Letters》;20150131(第1期);103-107 * |
| RN 1343179-52-1;Ukrorgsyntez Ltd.;《STN REGSITRY》;20111109 * |
| RN 1344251-09-7;Ukrorgsyntez Ltd.;《STN REGISTRY》;20111109 * |
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